title: Location of the CD8 T cell epitope within the antigenic precursor determines immunogenicity and protection against the Toxoplasma gondii parasite.
abstract: CD8 T cells protect the host from disease caused by intracellular pathogens, such as the Toxoplasma gondii (T. gondii) protozoan parasite. Despite the complexity of the T. gondii proteome, CD8 T cell responses are restricted to only a small number of peptide epitopes derived from a limited set of antigenic precursors. This phenomenon is known as immunodominance and is key to effective vaccine design. However, the mechanisms that determine the immunogenicity and immunodominance hierarchy of parasite antigens are not well understood. Here, using genetically modified parasites, we show that parasite burden is controlled by the immunodominant GRA6-specific CD8 T cell response but not by responses to the subdominant GRA4- and ROP7-derived epitopes. Remarkably, optimal processing and immunodominance were determined by the location of the peptide epitope at the C-terminus of the GRA6 antigenic precursor. In contrast, immunodominance could not be explained by the peptide affinity for the MHC I molecule or the frequency of T cell precursors in the naive animals. Our results reveal the molecular requirements for optimal presentation of an intracellular parasite antigen and for eliciting protective CD8 T cells.
authors.affiliation: INSERM, U1043 Toulouse, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Feliu
authors.forename: Virginie
authors.initials: V
authors.lastname: Vasseur
authors.forename: Harshita S
authors.initials: HS
authors.lastname: Grover
authors.forename: H Hamlet
authors.initials: HH
authors.lastname: Chu
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Brown
authors.forename: Jeremy
authors.initials: J
authors.lastname: Wang
authors.forename: Jon P
authors.initials: JP
authors.lastname: Boyle
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Robey
authors.forename: Nilabh
authors.initials: N
authors.lastname: Shastri
authors.forename: Nicolas
authors.initials: N
authors.lastname: Blanchard
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000502:physiology*; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D007739:L Cells; D051379:Mice; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D016052:Protozoan Vaccines / Q000235:genetics / Q000276:immunology*; D014122:Toxoplasma / Q000235:genetics / Q000276:immunology*
chemical_list: D000953:Antigens, Protozoan; D018984:Epitopes, T-Lymphocyte; C095047:GRA6 protein, Toxoplasma gondii; D015800:Protozoan Proteins; D016052:Protozoan Vaccines